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Maurizio Fava, MDDirector
Clinical Research ProgramExecutive Vice Chair
Department of PsychiatryExecutive Director
Clinical Trials Network and Institute (CTNI)Massachusetts General Hospital
Slater Family Professor of PsychiatryHarvard Medical School
Cognitive Impairment in Major Depressive Disorder as a Target for
Drug Development
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Disclosures (lifetime): Maurizio Fava, MDType Company
Advisory Board/Consultant
Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; AuspexPharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; CompellisPharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG;Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; PsylinNeurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.
Speaking/Publishing
Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories.
Research Support Abbot Laboratories; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; EuthymicsBioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; LichtwerPharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC;PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories
Stock/Other Financial Options
Equity Holdings: Compellis; PsyBrain, Inc.Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven.
Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.
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How do we Assess and Define Cognitive Impairment in MDD?
How Common is It?
What is its Impact on MDD?
Is Cognitive Impairment in MDD a Reasonable Target for Drug
Development?
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Objective vs Subjective Measures of Cognition
Performance on Standardized
Cognitive Tests
Self-Reported Levels of
Functioning
Self-Reported Perception of
One’s Cognitive and Executive
Function
Minus - The Norms are Population-Based and
Do Not Reflect Premorbid
Performance Levels
Plus - These are Objective Measures,
Relatively Devoid of Biases
Plus – Some of These Measures
Capture the Perception of Change From
Premorbid Levels
Minus – Depression and/or Anxiety May
Affect the Perception of Cognitive Function
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Objective Measures of Cognitive Impairment (CI) in Depression
Austin et al, Journal of Affective Disorders, 1992; 25, 21–29
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Major Depressive Disorder Is Associated With Broad Impairments on Neuropsychological Measures of Executive Function: A Meta-Analysis and Review.Snyder, Hannah
Psychological Bulletin. 139(1):81-132, January 2013.DOI: 10.1037/a0028727
Figure 1 Weighted mean effect sizes for all analyses. Error bars are 95% confidence intervals. Compared to healthy control participants, patients with major depressive disorder are significantly impaired on all tasks. Executive function (EF) composite measures are indicated with diamond symbols, and individual measures within each EF component by circle symbols in the same color. Pink circles indicate non-EF comparison measures. The solid gray vertical line indicates the psychomotor speed composite score effect size: Measures for which the lower error bar (95% confidence interval) does not pass the dashed line are significantly greater than 0, and those that do not pass the solid gray line have significantly larger effect sizes than the psychomotor speed effect size. Comp. = composite score; WCST = Wisconsin Card Sorting Test; TMT-B = Trail Making Test Part B; TMT-A = Trail Making Test Part A; ID/ED = Intradimensional/Extradimensional; WM = working memory; DMTS = delayed-match-to-sample; VF = verbal fluency.
Meta-Analysis of Studies Using Objective Measures of Cognitive Impairment (CI) in Depression
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Cognition Subscale of the CPFQ
Fava et al, Reliability and Validity of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire. Psychother Psychosom 2009;78:91–97
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Prevalence of Subjectively-Defined Cognitive Impairment in MDD
Subjective impairment
CPFQ (<moderately)NO
CPFQ (>markedly) YES
267 (58%)
195(42%)
TAK316
Fava et al, in preparation; this is a baseline, post-hoc analysis
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Differences in Depression Severity and Functioning in MDD with and without Cognitive Impairment
Subjectively
CPFQ (<moderately
impaired)n=267 (58%)
CPFQ (>markedlyimpaired)
n=195 (42%)
MADRS 31.5 ± 4.1 33.3 ± 4.3
SDS18.2 ± 5.3(n=169)
20.9 ± 6.2(n=134)
TAK316
Fava et al, in preparation; this is a baseline, post-hoc analysis
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How does Cognitive Impairment in Depression Relate to the Heterogeneity of MDD and its Various Symptoms?
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Do the Subtypes of MDD Affect Cognition Differently?
Major Depressive Disorder With
Atypical Features
Major Depressive Disorders With
Melancholic Features
Major Depressive Disorder With
Psychotic Features
Major Depressive Disorder With Irritability and Anger Attacks
Major Depressive Disorder with
Anxious Distress
Cognitive Impairment
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Relationship Between Depressive and Cognitive Symptoms in MDD
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What is the Overlap Between Subjective and Objective Cognitive Impairment in MDD?
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Distribution of MDD patients with Cognitive Impairment
CONNECT
47%53%
Subjective Self-reported Cognitive Impairment in MDD
≥ markedly impaired (+ Subj)
≤ moderately impaired (- Subj)
patients scoring at least markedly impaired (>5) on at least 2 of the 4 cognitive items in CPFQ
57%
43%
Objective Cognitive Impairment in MDD
≥ 1SD impaired in ≥2 test (+ Obj)
≤ 1SD impaired in > 2 test (- Obj)
patients scoring >1 SD below norm on 2 or more of DSST, TMT-B, CRT, One-back
28%
29%
19%
24%
Subjective AND/OR Objective Cognitive Impairment in MDD
+ Subj and + Obj - Subj and + Obj
+ Subj and - Obj - Subj and - Obj
(n=144)
(n=174)
(n=168)
(n=115)
(n=318)(n=283)
(n=259)
(n=343)
Fava et al, in preparation; this is a baseline, post-hoc analysis
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Differences in Depression Severity and Functioning in MDD with and without Cognitive Impairment
SubjectivelyCPFQ (<moderately
impaired)n=318 (53%)
CPFQ (>markedlyimpaired)
n=283 (47%)
MADRS 30.9 ± 3.5 32.5 ± 4.0
PDQ 37.4 ± 10.5 49.2 ± 9.1
UPSA 78.5 ± 12.3 77.9 ± 12.9
CONNECT
Objectively”Not/Less”
impaired (<1SD) n=259 (43%)
Impaired (>1SD) n=343 (57%)*
MADRS 31.6 ± 3.9 31.7 ± 3.8
PDQ 42.2 ± 11.3 43.5 ± 11.6
UPSA 80.6 ± 10.2 76.4 ± 13.9
*patients scoring >1 SD below norm on 2 or more of DSST, TMT-B, CRT, One-back
(Objectively impaired)
Fava et al, in preparation; this is a baseline, post-hoc analysis
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Do Antidepressant Therapies Adequately Address Cognitive Impairment in MDD?
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Changes in Neuropsychological Testing After Antidepressant Therapy in MDD
Chang et al, Brain, Behavior, and Immunity 26 (2012) 90–95
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Subjective Cognitive Improvement in MDD Remitters and non-Remitters
Baer et al, ANNALS OF CLINICAL PSYCHIATRY 2014;26(4):270-280
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Proportion of MDD Subjects with Residual Physical and Cognitive Deficits Based on CPFQ Scores (N=117)
Fava M et al, J Clin Psych 2006; 67: 1754-1759
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Percentages of Impairment in CPFQ Domains Among MDD Responders to SSRI Treatment (n=93)
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
Any Impairment
Minimal sxs
Moderate sxs
Freeman et al, in preparation
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Percentages of AE-Related Residual Impairment in CPFQ Domains Among MDD Responders to SSRI Treatment
0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
Adv Event %
Adv Event %
Freeman et al, in preparation
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Depression and Cognitive
Deficits are Independently
Related to Functional
Deficits in Mood Disorders
Bowie et al, Am J Psychiatry. 2010
Sep;167(9):1116-24.
b) Prediction of Community and Household Activities
a) Prediction of Work Skills
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Vortioxetine significantly improves cognitiveperformance even after correcting for effect on mood
Path-analysis shows that up to two thirds of the effect on cognition can be considered as independent effect, not mediated by improvement on mood
The Effects on Cognition Cannot Solely be Explained by the Improvement in Depressive Symptoms
Vortioxetine
MADRS
Direct effect
DSST
Indirect effect
VOR 10 VOR 20
DSST 66% 56%
VOR 10 VOR 20
DSST 34% 44%
Change from Baseline to Placebo (FAS, LOCF)
VOR 10mg
VOR20mg
Effect on DSST after correcting for effect on MADRS
2.59** 2.23**
0
2
4
6
8
10
12
14
Non-remittersMADRS>10
Non-respondersMADRS<50%
Mean
ch
an
ge f
rom
baselin
e in
D
SS
T c
orr
ect
nu
mb
er
of
sym
bo
ls
Pbo VOR 10mg VOR 20mg
*** ***
146 123 110
***
124 92 68
Vortioxetine significantly improves cognitive functionin both non-remitters and non-responders
FOCUS
McIntyre et al. Int J Neuropsychopharmacol 30 April 2014:1-11. Epub ahead of print
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• Correlation between SDS and CPFQ change in total score from baseline to endpoint in patients with MDD and residual apathy
Relationship between Changes in Functioning (SDS) and Cognition (CPFQ) in MDD Patients with Residual Apathy
Rothschild et al, Comprehensive Psychiatry 55 (2014) 1–10;
Baer et al, ANNALS OF CLINICAL PSYCHIATRY 2014;26(4):270-280
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• 40% to 55% of adults with MDD present with either subjective or objectively defined cognitive impairment
• The presence of cognition impairment in MDD is associated with greater illness severity and poorer functioning than MDD alone
• There is a poor correlation between core MDD symptoms and symptoms of cognitive impairment
Conclusions
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• Even among responders/remitters with MDD, residual cognitive impairment is common (30% to 40%)
• These residual symptoms are typically not due to the antidepressant therapy
• Changes in levels of functioning among MDD patients with residual symptoms are significantly accounted for by changes in cognitive symptoms
Conclusions (cont.)
